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The 2007 National Research Council Report "Toxicity Testing in the 21st Century: A Vision and A Strategy" recommended an integrated, toxicity pathway-oriented approach for chemical testing. As an integral component of the recommendation, computational dose-response modeling of toxicity pathways promises to provide mechanistic interpretation and prediction(More)
From a risk assessment perspective, DNA-reactive agents are conventionally assumed to have genotoxic risks at all exposure levels, thus applying a linear extrapolation for low-dose responses. New approaches discussed here, including more diverse and sensitive methods for assessing DNA damage and DNA repair, strongly support the existence of measurable(More)
Risk assessment methodologies in toxicology have remained largely unchanged for decades. The default approach uses high dose animal studies, together with human exposure estimates, and conservative assessment (uncertainty) factors or linear extrapolations to determine whether a specific chemical exposure is 'safe' or 'unsafe'. Although some incremental(More)
* a report of t 4 – the transatlantic think tank for toxicology, a collaboration of the toxicologically oriented chairs in Baltimore, Konstanz, General disclaimer: The opinions expressed in this report are those of the participants as individuals and do not necessarily reflect the opinions of the organizations they are affiliated with; participants do not(More)
Despite wide-spread consensus on the need to transform toxicology and risk assessment in order to keep pace with technological and computational changes that have revolutionized the life sciences, there remains much work to be done to achieve the vision of toxicology based on a mechanistic foundation. To this end, a workshop was organized to explore one key(More)
As part of a larger effort to provide proof-of-concept in vitro-only risk assessments, we have developed a suite of high-throughput assays for key readouts in the p53 DNA damage response toxicity pathway: double-strand break DNA damage (p-H2AX), permanent chromosomal damage (micronuclei), p53 activation, p53 transcriptional activity, and cell fate (cell(More)
A myriad of new chemicals has been introduced into our environment and exposure to these agents can damage cells and induce cytotoxicity through different mechanisms, including damaging DNA directly. Analysis of global transcriptional and phenotypic responses in the yeast S. cerevisiae provides means to identify pathways of damage recovery upon toxic(More)
A report on the joint Cold Spring Harbor/Wellcome Trust Meeting 'Interactome Networks', Hinxton, UK, 31 August-4 September 2005. High-throughput analyses are identifying the DNA, RNA, proteins and metabolites within a biological system with increasing accuracy and speed. As a result, we now have a relatively detailed understanding of the components that(More)
The application of toxicogenomics as a predictive tool for chemical risk assessment has been under evaluation by the toxicology community for more than a decade. However, it predominately remains a tool for investigative research rather than for regulatory risk assessment. In this study, we assessed whether the current generation of microarray technology in(More)
Toxicity screening of compounds provides a means to identify compounds harmful for human health and the environment. Here, we further develop the technique of genomic phenotyping to improve throughput while maintaining specificity. We exposed cells to eight different compounds that rely on different modes of action: four genotoxic alkylating (methyl(More)